1. Field of the Invention (Technical Field)
The present invention relates to uses of natriuretic peptide constructs which include a plurality of amino acid residues and one or more ring-constrained amino acid surrogates and optionally one or more prosthetic groups, for the prophylaxis or treatment of airway diseases, including but not limited to acute asthma and COPD.
2. Background Art
The natriuretic peptide system has been extensively explored since the identification of the human atrial natriuretic peptide (ANP) sequence and gene structure in 1984. ANP is sometimes also called “ANF”, or atrial natriuretic factor. ANP is part of the natriuretic peptide system, which in humans involves an ANP gene, which through differences in post-translational processing results in both ANP and urodilatin, a gene which produces BNP, or brain natriuretic peptide, and a gene which produces CNP, or c-type natriuretic peptide. ANP, urodilatin, BNP and CNP are each ring structures, with a 17 amino acid loop formed by a cysteine-cysteine disulfide linkage. ANP, urodilatin, BNP and CNP are closely related, differing by some five or six amino acids within the ring, though the N- and C-terminal tails are substantially different.
There are three known natriuretic peptide receptors called natriuretic peptide receptors A, B and C (NPRA, NPRB and NPRC). NPRA and NPRB are linked to guanylyl cyclases, while NPRC is a G-protein linked clearance receptor. ANP, BNP and CNP are the primary endogenous mammalian natriuretic peptides identified to date. However, there are a number of non-mammalian natriuretic peptides that have been identified and may have therapeutic application in mammals. Human ANP is also referred to as wild-type human ANP, hANP, ANP(1-28) and ANP(99-126) (the later referring to the relevant sequence within proANP(1-126), which is normally cleaved at Arg98-Ser99 in the C-terminal region during secretion).
Human ANP and BNP, including human BNP made by recombinant means, have been described as potentially having application in the treatment of asthma and related diseases, presumably through a mechanism related to increased guanylyl cyclase production, which in turn catalyzes the conversion of guanosine triphosphate (GTP) to 3′,5′-cyclic guanosine monophosphate (cGMP), resulting in increased cGMP levels. See, for example, Leuchte, H. H.; Michalek, J. et al., “Preserved pulmonary vasodilative properties of aerosolized brain natriuretic peptide,” Pulmonary Pharmacology & Therapeutics 22:548-533 (2009); Matera, M. G.; Calzetta, L. et al., “Relaxant effects of brain natriuretic peptide in nonsensitized and passively sensitized isolated human bronchi,” Pulmonary Pharmacology & Therapeutics 22:478-482 (2009); and Hamad, A. M.; Clayton, A. et al., “Guanylyl cyclases, nitric oxide, natriuretic peptides, and airway smooth muscle function.” Am. J. Physiol. Lung Cell Mol. Physiol. 285:973-983 (2003).
There are reports in the literature of human studies involving administration of human ANP and human BNP, such as by intravenous administration of BNP (Akerman, M. J.; Yaegashi, M. et al., “Bronchodilator Effect of Infused B-Type Natriuretic Peptide in Asthma.” Chest 130:66-72 (2006)), intravenous administration of ANP (Flüge, T.; Fabel, H. et al., “Urodilatin (Ularitide, INN): a potent bronchodilator in asthmatic subjects.” Eur. J. Clin. Invest. 25:728-36 (1995)), and inhaled ANP (Angus, R. M.; Millar, E. A. et al., “Effect of inhaled atrial natriuretic peptide and a neutral endopeptidase inhibitor on histamine induced bronchoconstriction.” Am. J. Respir. Crit. Care Med. 151:2003-2005 (1995).
There are, however, no reports of studies for treatment of asthma or related indications with compounds with natriuretic peptide functions, but which have increased resistence to enzymatic degradation, increased circulation half life, increased bioavailability, increased efficacy, prolonged duration of effect and combinations of the foregoing compared to human ANP or human BNP. While some reports have utilized an inhibitor, such as a neutral endopeptidase inhibitor, in combination with human ANP (see R. Angus et al., cited above), no reports have utilized compounds with the desired pharmacological properties.
Notwithstanding the large number of compounds that have been developed, none have been commercialized for the prophylaxis or treatment of airway diseases, including but not limited to acute asthma and COPD, and no natriuretic peptide compositions are reported to be in in active clinical development for the prophylaxis or treatment of airway diseases, including but not limited to acute asthma and COPD. There is a substantial need for products with improved characteristics, including improved potency, half-life, modes of administration, bioavailability or prolonged duration of effect, which products are effective for one or more airway disease therapeutic indications.